Abnormalities of prostate growth, including cancer and benign prostatic hyperplasia (BPH), produce some of the most common, costly, and devastating diseases occurring in men. Prostate cancer has exceeded lung cancer as the most commonly diagnosed cancer among men living in the United States, and is the second leading cause of cancer death in that population. American Cancer Society, Cancer Facts and Figures: 2004.
Early diagnosis of prostate cancer is central to effective treatment of the disease. Additionally, the ability to differentiate prostate cancer with metastatic potential from prostate cancer that is unlikely to metastasize is important.
Nuclear structural alterations are so prevalent in cancer cells that they are pathological markers of transformation for many types of cancer. Nuclear shape reflects the internal nuclear structure and processes, and is determined, at least in part, by the nuclear structure. Pienta, K. J. et al., Cancer Research 49:2525-2532 (1989). Structural components of the nucleus also play a central role in regulating important cellular processes such as DNA replication and transcription. Getzenberg, R. H. J Cell. Biochem. 55:22-31 (1994). The nuclear matrix is the framework; or scaffolding, of the nucleus, and consists of peripheral laminins, pore complexes, an internal ribonucleic protein network, and residual nucleoli (Berezney, R. and Coffey, D. S. Biochem. Biophys. Res. Comm. 60:1410-1417 (1974). It constitutes approximately 10% of the nuclear proteins and is virtually devoid of lipids, DNA and histones (Fey, E. G. et al., Critical Rev. in Eukaryotic Gene Expression 1:127-144 (1991).
Berezney first showed, while examining hepatoma nuclear matrix proteins (NMPs), that the nuclear matrix is altered in transformation. Berezney et al., Cancer Res. 39:3031-39 (1979). In addition, Fey and Penman demonstrated that tumor promoters induce a specific morphologic signature in the nuclear matrix-intermediate filament scaffold of kidney cells. Fey et al., Proc. Natl. Acad. Sci. USA 81:859-66 (1984). Fey and Penman further showed that the pattern of NMPs differed between normal and tumorigenic cell lines. Fey et al., loc. cit. 85:121-25 (1989); U.S. Pat. No. 4,885,236 and Re. 35, 727. Furthermore, an antibody to a nuclear matrix protein, termed NM-200.4, was raised from the breast carcinoma cell line T-47D. Weidner et al., Am. J. Path. 138:1293-98 (1991). This antibody reacts strongly with human breast carcinoma specimens as well as specimens from lung, thyroid, and ovarian cancers; however, it does not react with normal epithelial cells of similar origin, thereby raising the possibility of using certain anti-NMP antibodies as diagnostic tools.
While all cell types and physiologic states share the majority of NMDs, some NMPs appear to be unique to certain cell types or states. It has been demonstrated that the protein composition of the nuclear matrix is tissue-specific and represents a “fingerprint” of each cell and/or tissue type (Getzenberg, R. H. and Coffey, D. S. Mol. Endocrinol. 4(9):1336-1342 (1990)). Mitogenic stimulation and induction of differentiation alter the composition of nuclear matrix proteins and the resulting structure (Dworetzky, S. I. et al., Proc. Natl. Acad. Sci. USA 87:4605-4609 (1990); Stuurman, N. et al., Exp. Cell Res. 180:460-466 (1989)). Differences in NMP composition also are found among a number of human tumors, including renal (Konety, B. R. et al., J. Urol. 159:1359-1363 (1998)), breast (Khanuja, P. S et al., Cancer Res. 53:3394-3398, (1993)), colon (Keesee, S. K. et al., Proc. Natl. Acad. Sci. USA 91:1913-1916 (1994)), and head and neck tumors (Donat, T. L. et al., Otolaryngol. Head Neck Surg. 127:609-622 (1996)); McCaffrey, J. D. et al., Arch. Otolaryngol. Head Neck Surg. 123:283-288 (1997)).
U.S. Pat. No. 5,824,490 discloses certain nuclear matrix proteins associated with prostate tissue, including one denoted “PC-1 (prostate cancer-1),” which was used to identify prostate cancer. When human prostate samples were examined, nuclear matrix proteins were identified that (1) were present only in the normal prostate and were missing in both prostate cancer and BPH (normal pattern), (2) were found only in the prostate cancer cells and missing in the normal prostate and BPH (prostate cancer pattern), and (3) were found in both normal and BPH samples but were absent from prostate cancers. PC-1 (molecular weight 56 Kd and isoelectric point 6.58) represents an NMP seen only in human prostate cancer tissue and was consistently absent in all normal prostate and BPH samples.
Getzenberg et al. also reported the existence of an NMP derived from rat prostate, and designated AM-1. Getzenberg et al., Cancer Res. 51:6514-20 (1991). AM-1 exists in cancerous Dunning rat prostate tumors, but not in normal prostate, and has a molecular weight of 40 kD and a pI of 6.73. In a later abstract, Getzenberg et al. further characterized AM-1 as an NMP present only in metastatic rat prostate cancer cells, based on antibody studies in metastatic cell lines. Konety et al., Proc. Am. Assoc. Cancer Res., 37:73 (1996).
U.S. Pat. Nos. 5,874,539 and 6,030,793 and U.S. serial application No. 20020168695 disclose the use of proteins as biomarkers for diagnosing and monitoring the stage of malignancy of a prostate cell and for treating prostate cell proliferative disorders associated with the proteins. PC-1 is an example of these protein markers.
U.S. Pat. No. 6,090,559 discloses diagnostic techniques for detecting human prostate cancer through the use of genetic probes and methods. In particular, this patent discloses probes and methods for evaluating the presence of RNA species that are differentially expressed in prostate cancer relative to normal human prostate or benign prostatic hyperplasia.
U.S. serial application No. 20020164664, by Hlavaty, J. J. et al. (Matritech, Inc.), discloses a wide range of methods and compositions for detecting and treating prostate cancer. Specifically, the application provides target prostate cancer-associated proteins, which reportedly permit rapid detection, preferably before the occurrence of metastatic prostate cancer. These proteins are said to be detectable at a higher concentration in the serum of individuals with cancer than in the serum of individuals without cancer. Furthermore, they are said to be detectable at a higher concentration in individuals with disseminated prostate cancer than in individuals with localized (organ-confined) prostate cancer. One of the prostate markers purportedly permits detection of more than 90% of all prostate cancer, including cancers that are undetectable by prostate specific antigen (PSA) assays.
U.S. Pat. Nos. 5,989,826, 6,162,608, and 6,410,247B1 disclose methods for determining the degree of cell death in a tissue by detecting and quantitating soluble “interior” nuclear matrix proteins and protein fragments in body fluids and extracellular media. These methods purportedly are useful for monitoring the viability of cells and tissue, for evaluating the progress of a disease or its treatment, and for evaluating the cytotoxicity of unknown compounds. Also disclosed are methods for inducing the release of “interior” nuclear matrix proteins and protein fragments in soluble form from cells.
The use of prostate specific antigen (PSA) as a marker to screen individuals for prostate cancer has changed management of the disease and has permitted earlier detection in many men. The use of this marker, however, has caused many men to undergo repeated biopsies because of abnormally high PSA levels. Some of these men later prove to have clinical disease, but for many others, high PSA levels do not predict prostate cancer.
Beside the above-mentioned proteins, clinical and pathological staging and histological grading systems (e.g. Gleason's) have been utilized as prognostic indicators for patients, based on tumor differentiation or type of glandular pattern (Carter, H. B. and Coffey, D. S., J. Urol. 140:173-5 (1988)). However, these systems do not predict cancer progression.
As the preceding discussion illustrates, many unanswered questions still exist regarding the molecular etiology of prostate cancer. Current diagnostic and prognostic tools are unable to predict which men with prostate cancer will develop progressive and metastatic disease.
Thus, there remains a need for better prostate cancer biomarkers and for assays that are simple, rapid, sensitive, predictive and inexpensive, within or without clinical settings. There is also a need for diagnostic methods that can distinguish between aggressive and non-aggressive forms of prostate cancer and that can better identify and evaluate hyperplastic and malignant types of prostate cancers, preferably at an earlier stage.
More specifically, a need exists for a prostate biomarker that can identify individuals with prostate cancer even when the individuals' biopsy samples are morphologically negative. There is a also a need for corresponding antibodies, as an adjunct to pathologic examination of prostatic biopsies, to detect prostate cancer earlier, and thereby avoid or reduce the need for repeated biopsies,.